tbuckley/cabot-search huggingface dataset:
A phase I study of CPI-613 (devimistat) in combination with chemoradiation in patients with pancreatic adenocarcinoma.
Authors: Mandana Kamgar, Husain Yar Khan, Amro Aboukameel, Sahar Bannoura, Brian Y. Chung, Aniko Szabo, Yiwei Li, Mohammed Najeeb Al Hallak, Philip Agop Philip, Ben George, Kathleen K. Christians, Douglas B. Evans, Susan Tsai, Beth Erickson, Sanjeev Luther, Asfar S. Azmi, William A. Hall
Journal: Journal of Clinical Oncology (2023)

TPS760 Background: Local tumor progression is a cause of significant mortality and morbidity in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). Effective approaches to achieve durable local control are urgently needed. Metabolic reprogramming and enhanced mitochondrial function, both hallmarks of PDAC, are known contributors to chemo- and radio-resistance. CPI-613, a lipoic acid analog that selectively inhibits components of the Krebs cycle in tumors, showed promising preclinical synergy in combination with gemcitabine and radiation therapy (gem-RT). Methods: We describe a single-arm, single-center, open-label, phase I study designed to determine the maximum tolerated dose of CPI-613 when used concomitantly with gemcitabine and intensity modulated radiation therapy (IMRT) for local control of PDAC. CPI-613 will be administered once weekly by intravenous infusion over approximately 2 hours at a starting dose of 500 mg/m2 and dose-escalated/de-escalated using a Bayesian optimal interval design. Gemcitabine will be given once weekly at 400 mg/m2 dosage and IMRT as 54 Gray (Gy) in 30 fractions (1.8 Gy per fraction) with five fractions given per week. Up to 24 patients will be enrolled for the study after meeting the following main eligibility criteria, which include: pathologically confirmed PDAC; inoperable disease that by institutional pancreatic multidisciplinary tumor board or multidisciplinary review are considered to benefit from definitive local control of the primary tumor; ECOG of 0-2; and adequate organ and marrow function after completion of intended systemic chemotherapy. The secondary objectives are to determine the recommended phase II dose of CPI-613 when used with gem-RT, safety and tolerability of CPI-613-gem-RT, overall survival, local progression-free survival (PFS), overall PFS, patient-reported quality of life after treatment, and late gastrointestinal toxicities following treatment with CPI-613-gem-RT. Clinical trial information: NCT05325281 . Support: Cornerstone Pharmaceuticals. [Table: see text]
Examination of antagonistic metabolic reactions and nicotinamide/methylnicotinamide as a biomarker in gastric cancer.
Authors: Min Shi, Yu Jiang, Yawen Wang, Qiong Huang, Qijing Wu, Guofeng Chen, Bishan Liang, Jiao Wang, Shaowei Li, Jianhua Wu, Li Sun, Jian Guo, Wangjun Liao
Journal: Journal of Clinical Oncology (2023)

442 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the therapy pattern of advanced gastric cancer (GC), but the efficacy is still unsatisfactory. The role of metabolism in the immune landscape of tumor microenvironment (TME) has been emphasized for the past few years. As the mediators of cellular interactions in TME, more metabolic biomarkers and their predictive value remain to be revealed. Methods: Metabolite activity scoring gene sets were constructed based on metabolite-protein interaction network. Integrated metabolite profile was collected from metabolic reactions in KEGG database. Transcriptome of ACRG (n=299) and anti-PD-1 cohort (PRJEB25780, n=45) were utilized to generate metabolite activity scores via GSVA algorithm. Cox regression was performed to calculate the hazard ratio (HR) to overall survival of metabolites in each metabolic reaction. Plasma samples (n=55) were obtained to measure nicotinamide metabolites from GC patients in Nanfang Hospital before and after ICIs treatment. Results: 78 metabolic reactions (78/6429) with opposite prognostic value among metabolic substrates and products were identified via the antagonistic metabolism screening workflow. Notably, nicotinamide (NAM)-methylnicotinamide (MNAM) (KEGG REACTION: R01269) showed significant antagonistic relationship (NAM, HR=0.76, 95% CI: 0.64-0.89, P&lt;0.001; MNAM, HR=1.28, 95% CI: 1.09-1.49, P=0.002). NNMT, the rate-limiting enzyme catalyzing the formation of MNAM from NAM, was also correlated with poor prognosis (log-rank P=0.013). In terms of therapeutic prediction, NAM/MNAM ratio in plasma of GC patients was significantly correlated with anti-PD-1 response (PR vs SD/PD, median NAM/MNAM ratio (ng·mL -1 /ng·mL -1 ) = 26.76 vs 10.40, P&lt;0.0001). Compared with baseline, decreased plasma NAM/MNAM ratio was found in all (7/7) PR patients ( P=0.0011), while 73.33% (11/15) of non-responders showed a higher NAM/MNAM ratio after ICIs treatment ( P=0.0283). Correlation analysis of key metabolites with TME cells revealed that MNAM activity score was positively correlated with fibroblasts, MDSCs and M2 macrophages infiltration (Pearson correlation: R=0.60, P&lt;0.001; R=0.42, P&lt;0.001; R=0.34, P&lt;0.001), suggesting that MNAM has a potential impact on immune-suppressive cells recruitment and functions. Conclusions: Nicotinamide metabolism was an indicator of prognosis in GC patients. Circulating NAM/MNAM ratio can be a novel metabolic biomarker in dynamic monitoring for ICIs therapy.
Impact of COVID-19 pandemic on pancreatic cancer disparities and outcomes in Florida.
Authors: Alexander Lim, Guettchina Telisnor, Zhongyue Zhang, XiangYang Lou, Ibrahim Nassour, Ramzi Salloum, Sherise C. Rogers
Journal: Journal of Clinical Oncology (2023)

667 Background: Pancreatic cancer (PDAC) is the third-leading cause of cancer death in the United States. Florida had a high infection rate with several peaks throughout 2020 and 2021. The first aim of this study is to evaluate the impact of the COVID-19 pandemic on survival time, rate of surgical resection, and time to treatment of newly diagnosed pancreatic cancer in Florida. The second aim was to assess whether disparities with respect to race, age, income, and gender were exacerbated in newly diagnosed pancreatic cancer via stratified analysis of pandemic groups. Methods: This retrospective study included patients identified by OneFlorida+ Clinical Research Network, a statewide data trust, who were newly diagnosed with pancreatic adenocarcinoma via ICD 10 coding from January 1 st , 2017 to October 31st, 2020. Patients were compared between 3 cohorts based on date of pancreatic cancer diagnosis: pre-pandemic (01/01/2017- 09/30/2019), transition (10/01/2019-02/28/2020), and pandemic (03/1/2020-10/31/2020). Patients with a diagnosis of neuroendocrine carcinoma were excluded. Results: 934 unique patients were identified for analysis, of whom 81.3% were in the pre-pandemic cohort, 8.2% in the transition cohort, and 10.5% in the pandemic cohort. The racial distribution was 19.4% African American, 70.2% Caucasian, 0.7% Asian, 8.2% of Other races, and 1.3% reported unknown race or refused to answer. The median age was 67 years (range, 27–89 years). Gender was even. The median income was $52,915 (range, $23,704–$124,821). The differences in overall survival were not significant for age and gender across the 3 groups. Patients with income &lt;$53,000 had significantly lower survival time across all groups. African Americans had significantly lower survival time in the pre-pandemic and transition cohort (p&lt; .005), but Caucasians had the lowest survival time for the pandemic group (p &lt;.005). 60.2% of early-stage patients did not have surgery and the group distribution was 64.2% pre-pandemic, 48.5% transition, and 44.4% pandemic (p&lt; 0.027). Time to treatment was not significant across all groups and demographics. Conclusions: This study found a decrease in diagnosis, survival rate for some groups, and surgical resection rates during the COVID-19 pandemic in Florida. Resource planning should target these disparities in income and race.[Table: see text]
Delta radiomic parameters for the evaluation of liver metastases in patients with colorectal cancer treated with cetuximab rechallenge plus avelumab in the CAVE mCRC study.
Authors: Giulia Martini, Valerio Nardone, Davide Ciardiello, Marco De Chiara, Teresa Troiani, Luca D'ambrosio, Stefania Napolitano, Claudia Cardone, Chiara Cremolini, Filippo Pietrantonio, Evaristo Maiello, Antonio Avallone, Salvatore Cappabianca, Fortunato Ciardiello, Alfonso Reginelli, Erika Martinelli
Journal: Journal of Clinical Oncology (2023)

241 Background: We performed a retrospective analysis of metastatic colorectal cancer (mCRC) patients enrolled in CAVE trial. Cave mCRC is a single arm, academic, multicenter, phase II trial that evaluated the efficacy of cetuximab rechallenge plus avelumab in mCRC patients. Methods: CT imaging of patients were collected and retrospectively analysed. Inclusion criteria included evidence of liver metastases that could be measured and segmented, availability of an enhanced contrast phase at baseline and restaging CT imaging (within 3 months from baseline). The gross tumor volume (GTV) of liver metastases was evaluated at both baseline and first restaging CT. Multiple texture parameters were extracted with LifeX Software, and delta-texture analysis (D-TA) was calculated as percentage variations in the two time points. Patients were divided in a training cohort (coordinating center, University of Campania “L. Vanvitelli”) and validation cohort (other centers involved in CAVE mCRC trial). Patients were further divided in responders/non-responders according to median progression free survival (mPFS). ROC curve were calculated to obtain a cut-off. Survival analysis of progression free survival (PFS) and overall survival (OS) with Kaplan-Meier method was used in the two subgroups to test the cut-off found with the methods previously described. Results: The original dataset of CAVE mCRC protocol included 77 patients. Liver metastasis were present in 55 patients (71%); after application of inclusion and exclusion criteria, a total of 42 patients were included in the current analysis. The training cohort consisted of 22 patients (for a total of 32 liver metastasis) and the validation cohort of 20 patients (for a total of 28 liver metastasis). After Bonferroni correction, the only D-TA parameters that significantly correlated with mPFS in the training cohort were EntropyHistogram (p:0,021), HomogeneityGLCM (p&lt;0,001) and Dissimilarity GLCM (p:0,002). At multivariate analysis only HomogeneityGLCM resulted significant both in training (p:0,001, OR 0,1) and validation cohort (p:0,021, OR 0,3). ROC curves were generated and the cut-off of HomogeneityGLCM was equal to 0. Patients who developed a reduction of HomogeneityGLCM at first restaging CT scan showed a better PFS and OS (in both training and validation cohorts). Conclusions: Our results suggest that D-TA parameter such as HomogeneityGLCM is able to discriminate better survival outcomes in patient treated with cetuximab rechallenge plus avelumab, further prospective investigations are needed. [Table: see text]
Clinical significance of D-amino acid profile for cancer detection in early stage and prediction of efficacy of nivolumab in gastric cancer.
Authors: Kai Tsugaru, Tomohisa Sujino, Masashi Mita, Jumpei Sasabe, Akihiko Chida, Yosuke Harada, Kenro Hirata, Yasutaka Sukawa, Motohiko Kato, Hirofumi Kawakubo, Yasuo Hamamoto, Takanori Kanai
Journal: Journal of Clinical Oncology (2023)

453 Background: Some metabolites from gut microbiota are reported to associate with immunotherapy response. D-amino acids (D-AAs), enantiomer of L-amino acids (L-AAs), mainly produced by gut microbe and brain, are rare but important metabolite in mammals. Little is known about their biological and immunological significance in cancer patients (pts) as its difficulty of stable measurement. Methods: We first analyzed L/D-AAs in plasma of pts with each disease stage of gastric cancer (GC) before treatment, then compared with healthy control (HC). Second, we analyzed L/D-AAs in plasma of advanced GC pts planned nivolumab (NIVO) monotherapy, and compared among two groups divided based on treatment efficacy of progressive disease (PD) or non-PD. All pts with GC and HC were recruited in Keio University Hospital from October 2017 till March 2022. Concentration of L/D-AAs was measured with Two-Dimensional HPLC-MS/MS System. Results: In the first part, 108 pts with GC before treatment and 87 HC were recruited. D-Ser, D-Asn, D-Ala, D-Pro were detected in plasma of both pts with GC and HC, and their concentration was significantly higher in GC pts rather than in HC, even in pStage 1 ( p&lt;0.0001 of each D-AA, values in table). D-Ser showed an increasing trend as the disease stage progressed. The AUC value of ROC curve to discriminate Stage 1 GC pts from HC were 0.976 with D-AAs. In the second part, 28 pts with advanced GC before NIVO monotherapy were recruited. The best response was PD in 10 pts, and non-PD in 18 pts. D-Ser and D-Asn in plasma were significantly higher in PD group rather than non-PD group ( p=0.0025 and p=0.0158, respectively). The AUC value of the ROC curve discriminating NIVO PD was highest for the equation mainly with D-Ser at 0.933. Pts with poor progression free survival (PFS) and overall survival (OS) could be distinguished by the determined cutoff value of the equation [median PFS: 1.1m vs 3.8m, HR 5.1 ( p=0.0003), median OS: 3.4m vs 18.9m, HR 7.1( p=0.0010)]. Conclusions: D-AAs in plasma significantly increased in pts with GC rather than HC even in early stage. Moreover, higher D-Ser in plasma associated with poor efficacy and prognosis of NIVO in GC pts. We firstly reported D-AA is a novel biomarker of both cancer detection and efficacy of NIVO.[Table: see text]
Clinicopathologic features of early-onset (EO) esophageal and gastric cancers.
Authors: Sarah Elizabeth Lochrin, Oana Deac, Jacintha O'Sullivan, Moya Cunningham, Narayanasamy Ravi, Claire L Donohoe, Grainne M. O'Kane, John V. Reynolds, Maeve Aine Lowery
Journal: Journal of Clinical Oncology (2023)

472 Background: The rates of gastric (GC) and esophageal adenocarcinoma (EA) among individuals younger than age 50 years have increased by 30% and 50%, respectively, over the past three decades in the US. There is limited information on incidence and demographics for EO esophageal and gastric cancer in Europe. Methods: We conducted a retrospective review of the prospectively maintained upper gastrointestinal (UGI) cancer database in St James’s Hospital (SJH), the National Centre for Oesophageal and Gastric Cancer in Ireland. We reviewed all cases diagnosed with esophageal cancer (EC) and gastric cancer (GC) less than or equal to 50 years of age from 2000 to 2021. Results: From 2000 to 2021, 374 EO EA &amp; GC cases were identified, 8% of the 4663 total EC &amp; GC cases. The results are presented in the table. Conclusions: The major presenting symptoms for EO-UGI cancer were dysphagia, weight loss and dyspepsia, further investigation is warranted in young patients presenting with these symptoms, even in the absence of elevated BMI or other known risk factors for malignancy. A high proportion have advanced disease at diagnosis despite good PS and clinical outcomes are poor. There is a critical need to understand the pathogenesis of EO-UGI cancers to determine optimal strategies for prevention and management.[Table: see text]
Casper: A phase I, open-label, dose finding study of calaspargase pegol-mnkl (cala) in combination with cobimetinib (cobi) in locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Charles D. Lopez, Adel Kardosh, Emerson Yu-sheng Chen, Guillaume Joe Pegna, Shaun Goodyear, Erin Taber, Brindha Rajagopalan, Exodus Edmerson, Johnson Vo, Anna Jackson, Tasha Gingerich, Anne Fahlman, Diane Ventura, Preeyam Roy, Dove Keith, Gordon B. Mills, Jonathan Brody, Brett C. Sheppard, Rosalie C. Sears, Ze'ev Ronai
Journal: Journal of Clinical Oncology (2023)

TPS772 Background: Metabolic adaptation provides rapidly dividing cancer cells the flexibility to maintain homeostasis as nutrient supplies are continuously exhausted in the tumor microenvironment. Asparagine synthetase (ASNS) catalyzes ATP-dependent biosynthesis of the non-essential amino acid asparagine from aspartate and glutamine. Cells lacking ASNS, however, are auxotrophic for asparagine. Use of L-asparaginase (ASNase) to promote asparagine starvation in PDAC and other solid tumors with low ASNS levels is a rationale treatment strategy; however, aberrant RAS/MAPK signaling can circumvent effects of ASNase. Preclinical data shows that targeted inhibition of MAPK signaling along with ASNase is active against PDAC; however, this has not been tested in patients to date. Methods: CASPER is an open-label, phase IB, single-arm, dose-escalation study to evaluate the safety and tolerability of combining cala and cobi in patients with locally-advanced or metastatic PDAC. Participants receive cala and cobi at assigned dose level. The study uses a Bayesian Optimal Interval (BOIN) design to determine the maximum tolerated dose (MTD) for the combination of study agents. Up to 15 participants will be enrolled and treated, with a cohort of 3 participants assessed before a decision is made to escalate, de-escalate, or maintain the current dose level before initiating the next cohort. MTD is defined as the dose level where dose-limiting toxicity (DLT) probability is closest to the target toxicity rate of 30% after applying isotonic regression to the observed dose-level-specific DLT rate. Per BOIN, the dose level is escalated, maintained, or de-escalated based on comparisons of the observed DLT rate and pre-specified boundaries (0.236, 0.359). Starting in Cycle (C) 1, patients receive cobi (at assigned dose level) for Days (D) 1-14, and their assigned dose of cala on D1 of each 21-day cycle. If the combination of cala and cobi is tolerated and does not incur DLTs, participants will continue receiving their assigned dose of cala and cobi until evidence of disease progression, unacceptable toxicity, or study withdrawal. The DLT period starts on C1D1 and ends C2D21. Secondary endpoints include preliminary assessment of overall response rate (ORR), disease control rate (DCR), and mean levels of plasma ASNase. Paired tumor biopsies and serial blood will be used for exploratory objectives combining deep multi-omic analytics with clinical data. The trial is currently open with 1 patient enrolled at time of submission. Clinical trial information: NCT05034627 . [Table: see text]
Multicenter retrospective study of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) for vulnerable patients with pretreated metastatic colorectal cancer (mCRC): WJOG14520G (TWILIGHT).
Authors: Seiichiro Mitani, Yosuke Kito, Hisato Kawakami, Shinichi Nishina, Toshihiko Matsumoto, Takao Tsuzuki, Yudai Shinohara, Hozumi Shimokawa, Ryosuke Kumanishi, Takashi Ohta, Shinya Kimura, Takeshi Kawakami, Tomohiro Nishina, Hiroko Hasegawa, Kohei Akiyoshi, Yasutaka Chiba, Kentaro Yamazaki, Shuichi Hironaka, Kei Muro
Journal: Journal of Clinical Oncology (2023)

121 Background: In the phase III SOLSTICE study, FTD/TPI plus BEV showed similar efficacy to capecitabine plus BEV as first-line treatment for patients with mCRC ineligible for full-dose combination chemotherapy with oxaliplatin [OX] or irinotecan [IRI] (intensive therapy). We evaluated clinical outcomes of FTD/TPI plus BEV as second- or later lines treatment for vulnerable patients, who were defined to be intolerant to intensive therapy. Methods: This was a multicenter retrospective study of vulnerable patients with unresectable mCRC who received FTD/TPI plus BEV as second- or later lines treatment between May 2014 and October 2020. Main eligibility criteria were histologically proven adenocarcinoma, ECOG PS 0-2, prior chemotherapy for unresectable disease, considered intolerant to intensive therapy, and underwent FTD/TPI plus BEV without prior exposure to at least one key cytotoxic agent (fluoropyrimidines [FP], OX, or IRI). Results: Of 96 patients enrolled from 26 Japanese hospitals, 93 patients were evaluable. Patient characteristics were as follows: median age, 79 years (range 21-90); male, 53%; ECOG PS 0-1, 89%; right-sided primary tumor, 30%; primary tumor resection, 86%; RAS mutant, 63%; BRAF mutant, 1%; second-line treatment, 80%; prior exposure to FP 100%, OX 50%, and IRI 15%. Main reasons for intolerance to intensive therapy were older age (65%), poor PS (20%), and renal failure (5%). Initial dose of FTD/TPI was reduced in 30 (32%) patients. The response rate was 5% and disease control rate was 68%. With median follow-up of 21.6 months, the median progression-free survival, time to treatment failure, and overall survival were 6.3, 4.5, and 18.6 months, respectively. Major grade &gt;3 adverse events were neutropenia (54%), anemia (20%), thrombocytopenia (9%), hypertension (7%), and febrile neutropenia (2%). No treatment-related deaths were observed. The treatment was discontinued in 89 patients due to disease progression (n = 72), patient’s refusal (n = 10), and adverse events (n = 6). After FTD/TPI plus BEV, chemotherapies such as regimens including IRI or OX (n = 20), regorafenib (n = 16), and anti-EGFR antibody monotherapy (n = 7) were performed in 42 patients. Conclusions: FTD/TPI plus BEV as second- or later lines treatment for vulnerable patients with mCRC showed promising clinical activity and acceptable safety profile. This study suggested that FTD/TPI plus BEV could be a treatment option for vulnerable patients with pretreated mCRC. Clinical trial information: UMIN000044136 .
Does distance traveled impact management and outcomes in patients with pancreatic adenocarcinoma who are candidates for curative resection?
Authors: Mariam Khan, Grant Backer, Andrew Alvarado, Susanna Wang, Deepthi Devireddy, Jessica Parker, M Mura Assifi, Mathew Chung, G Paul Wright, Sreenivasa R Chandana
Journal: Journal of Clinical Oncology (2023)

668 Background: We investigated the impact of distance traveled to a tertiary care center for treatment in the management and outcomes of patients with pancreatic adenocarcinoma (PDAC). Methods: Patients treated for operable PDAC at a single institution from 2010-2019 were retrospectively reviewed. Data was collected on demographics, tumor characteristics, social determinants of health, diagnostic/staging work-up, surgical details, and outcomes. Patients were divided into three groups based on distance from our institution: Group A, &lt;10 miles, Group B, &gt;11-50 miles, or Group C, &gt; 50 miles. The primary outcome was two-year survival. Results: There were 314 patients included. The mean age was 67.6+10.5 years. Patients farther from the hospital were less likely to undergo CT with contrast (Group B 97.1% versus Group C 89.0%, p = 0.02) and more likely to get MRCP (Group A 17.0% versus Group C 36.3%, p = 0.01) for staging. Distance was also associated with increased time to first encounter with medical or surgical oncology (Group A 6 days versus Group C 9 days, p = 0.02) and treatment initiation (Group A 22 days versus Group C 28 days, p &lt; 0.001). There were no differences in postoperative complications, length of stay, discharge disposition, or follow-up. Two-year survival was better in Group A than Group B (54.1% versus 35.5%, p = 0.04). There was no difference in five-year survival. In the multivariable model for two-year survival, no patient or tumor characteristics were significant. Conclusions: In this PDAC population, patients living farther from a tertiary cancer center had worse two-year postoperative survival. Prospective studies in this area are needed.